SETD8 is a lysine methyltransferase that monomethylates p53 in human cell lines. The monomethylation by SETD8 suppresses p53-mediated transcriptional activation of highly responsive target genes, such as p21 and PUMA but it has little influence on weak p53 targets. Depletion of SET8 augmented the proapoptotic and checkpoint activation functions of p53, and SETD8 expression is downregulated during DNA damage.